Angiotensin converting enzyme is responsible for the conversion of the decapeptide angiotensin I to the potent vasopressor, angiotensin II, an octapeptide. Peptide compounds derived from snake venom and ranging from pentapeptide to nonapeptide have been found to be potent inhibitors of the converting enzyme, see, for example, L. J. Green, J. M. Stewart and S. H. Ferreira, Pharmacol. Res. Comm., 1, 159 (1969); M. A. Ondetti, N. J. Williams, E. F. Sabo, J. Pluscec, E. R. Weaver and O. Kocy, Biochemistry, 10, 4033 (1971). The further work of D. W. Cushman, J. Pluscec, N. J. Williams, E. R. Weaver, E. F. Sabo, O. Kocy, H. S. Cheung and M. A. Ondetti, Experientia, 29, 1032 (1973) teaches that various smaller peptides such as tripeptides also display useful inhibitory potency against the converting enzyme. For example, a tripeptide such as phenylalanyl-alanyl-proline showed a substantial degree of activity. The nonapeptide above was shown to lower blood pressure in animal models of renovascular hypertension, see, for example, S. L. Engel, T. R. Schaeffer, M. H. Waugh and B. Rubin, Proc. Soc. Exptl. Biol. Med., 143, 483 (1973); E. E. Muirhead, B. Brooks and K. K. Arora, Lab Invest. 30, 129 (1974) and in humans with various forms of hypertension, see, for example, H. Gavras, H. R. Brunner, J. H. Laragh, I. Gavras and R. A. Vukovich, New Engl. J. Med., 291, 817 (1974). The lack of oral activity, however, has limited the use of the nonapeptide as a therapeutic drug for treatment of hypertension. Thus the various peptides have not found clinical acceptance because of their apparent instability to hydrolytic media such as the various peptidases of the gut.
It is an object of this invention to provide novel compounds having potent inhibitory properties against the angiotensin converting enzyme. A further object is to provide compounds of this character which are reasonably stable to hydrolytic media and thus allow attainment of therapeutically useful levels of the compound in the blood.